A CONVERSATION WITH: James McKerrow; A Lab Builds Better Barriers Against Invading Parasites

By CLAUDIA DREIFUS

Published: July 26, 2005

Dr. James H. McKerrow hails from a long line of activists. His father was a social worker and an advocate for abused children. His mother was a nurse. An ancestor was a prominent abolitionist who helped slaves make their way to freedom in Canada.

Dr. McKerrow, 57, a pathologist and biochemist, lives out his family's traditions in the way he does his science. As the director of the Sandler Center for Basic Research in Parasitic Diseases at the University of California, San Francisco, he has been looking for -- and finding -- promising new treatments for parasitic infections that sicken millions of people in the developing world.

He spoke of his life, work and commitments in a interview during a stopover in New York City on his way home from a conference in Prague. He lives in San Francisco with his wife and two children.

Q. How did parasites become your passion?

A. Till about 15 years ago, I was doing research in a unrelated field, cancer. Then one night, I attended a lecture where I heard parasitologist Donald Heyneman speak about schistosomiasis, sometimes called bilharzia.

Heyneman was this Indiana Jones-type figure. He traveled to remote parts of the world where people still lived as hunter-gatherers, and studied how parasitic diseases affected them. In this lecture, he told how these organisms find you, how they pierce the skin and get into the body to live off of it -- without anything stopping them.

I'd been researching how cancer cells get through tissue, how they invade organs. This seemed much more amazing. This was a multicellular entity, a fairly large organism invading through skin. I was completely intrigued. I began to think about parasites -- whom most of us never think about at all -- as these really remarkable creatures.

Q. What do you find remarkable about parasites?

A. Well, they have evolved to have an intimate relationship with us -- more intimate than that of most diseases caused by bacteria or viruses. Think about the schistosome. It is often a half-inch long and it can live in the bloodstream for up to 30 years. A researcher has to ask, ''Why didn't the immune system get rid of this?'' Obviously, these organisms have figured out ways to circumvent the immune system and even exploit it.

Beyond being intellectually interesting, researching parasites appealed to my social conscience. Parasitic diseases are a big factor hobbling economic development in the third world.

In some parts of Africa, nearly everyone will be infected.

They won't be able to work full days. I want to do the kind of science that can help solve some of humanity's problems. Pure research was never enough. With parasites, I can merge my scientific curiosity with a desire to do good.

Q. How many people are affected by parasitic disease?

A. Hundreds of millions of people. With intestinal worms, a billion. In the West, we think a lot about diabetes and rightly so. But it only affects about a hundred million people. Globally, there are probably 250 million with schistosomiasis and 500 million with malaria. At my lab, we are working on the five neglected diseases of mankind -- malaria; schistosomiasis; leishmaniasis, aka the Baghdad boil; African sleeping sickness; and Chagas' disease.

Q. Why are certain diseases ''neglected?''

A. The big pharmaceutical companies have little interest in new research on these diseases. Their thrust is for expensive drugs that the affluent will take for long periods of time -- drugs for diabetes or osteoporosis, for instance.

The Gates Foundation has been putting a lot of effort into malaria, but that's a nonprofit. The bottom line: parasites mostly infect poor people living in poor countries.

Q. How does a researcher get past a roadblock like the lack of interest of pharmaceutical companies?

A. At my lab, we've been circumventing the problem by becoming a kind of pharmaceutical company ourselves. With funding from the Sandler Family Foundation, we've purchased machines that facilitate new styles of research.

There's this new computerized robot that permits a researcher to quickly assay thousands of substances to see if they might be effective against parasites.

In the past, if you wanted to test 1,000 compounds, you'd need 1,000 scientists pouring chemicals between test tubes, back and forth, back and forth. With this new technology, you can test 1,000 substances in a couple of hours.

After we got the machine, we ran ''libraries'' of F.D.A.-approved drugs for other uses through it. Very quickly, we've found 90 with promise as antiparasitic agents.

A. We tried Cialis, but it wasn't a hit. For African sleeping sickness, we got hits for a well-known antidepressant, a muscle relaxant, an antibiotic and ''old man's beard,'' a plant compound sometimes used in traditional Chinese medicine.

The muscle relaxant and the anti-depressant are particularly promising because they bypass the blood-brain barrier, a requirement in this neurological disease. Since these drugs are approved for other uses, it shortcuts the process of getting them out there. Of course, they'll have to be tested on infected people.

By the way, we've had good luck on Chagas' disease, too -- though we tried something different there. We actually have a drug candidate that has already successfully passed animal testing and will soon be ready to be tested on people.

Q. Chagas' disease is a huge problem in Latin America, is it not?

A. It's the leading cause of heart disease there. Right now, there are two drugs for it and they have very severe side effects.

With Chagas', we used X-ray crystallography to visualize at an atomic level an enzyme within the parasite. This enzyme is necessary for the parasite to invade the heart muscle. Once we visualized the enzyme, we could modify the inhibitor to disable the enzyme.

A friend of mine, a chemist at Celera, had been working on an arthritis drug -- which turned out to be the effective enzyme inhibitor with Chagas'. Celera has now kindly let their patent lapse so that we can pursue the drug's development.

Q. How do you transform your findings into actual medications that people can use?

A. Normally, the pharmaceutical companies did that. Because of the economics, they're not going to get directly involved. In the last few years, philanthropies working on global health have set up new systems for drug manufacturing.

You can contract directly with a drug manufacturing facility in Ireland, Puerto Rico or India. Our center has also hired two people from private industry who are savvy about how to set up clinical trials. We can have the drugs made ourselves and test them ourselves.

So we've now got possible treatments for two of mankind's five neglected diseases.

Wow -- two down and three to go! That's made us think our approach can succeed. It's really fun to do this science now because the application is not far away.

And we hope we're showing something to the next generation of scientists about how to be both clever and idealistic.

Photo: Dr. James H. McKerrow examines a tapeworm, one of the many parasites that can attack the human body. (Photo by Peter DaSilva for The New York Times)